tbuckley/cabot-search huggingface dataset:
A hierarchical vascularized engineered bone inspired by intramembranous ossification for mandibular regeneration
Authors: Xin Ye, Jianxiang He, Shaolong Wang, Qianglong Han, Dongqi You, Bin Feng, Feiya Zhao, Jun Yin, Mengfei Yu, Huiming Wang, Huayong Yang
Journal: International Journal of Oral Science (2022)

Mandibular defects caused by injuries, tumors, and infections are common and can severely affect mandibular function and the patient's appearance. However, mandible reconstruction with a mandibular bionic structure remains challenging. Inspired by the process of intramembranous ossification in mandibular development, a hierarchical vascularized engineered bone consisting of angiogenesis and osteogenesis modules has been produced. Moreover, the hierarchical vascular network and bone structure generated by these hierarchical vascularized engineered bone modules match the particular anatomical structure of the mandible. The ultra-tough polyion complex has been used as the basic scaffold for hierarchical vascularized engineered bone for ensuring better reconstruction of mandible function. According to the results of in vivo experiments, the bone regenerated using hierarchical vascularized engineered bone is similar to the natural mandibular bone in terms of morphology and genomics. The sonic hedgehog signaling pathway is specifically activated in hierarchical vascularized engineered bone, indicating that the new bone in hierarchical vascularized engineered bone underwent a process of intramembranous ossification identical to that of mandible development. Thus, hierarchical vascularized engineered bone has a high potential for clinical application in mandibular defect reconstruction. Moreover, the concept based on developmental processes and bionic structures provides an effective strategy for tissue regeneration.
PB1837: ADDITION OF A THIRD, NON-TARGETED, AGENT TO CYTARABINE- AND ANTHRACYCLINE-BASED INDUCTION CHEMOTHERAPY FOR ACUTE MYELOBLASTIC LEUKEMIA INCREASES COMPLETE REMISSIONS AND TREATMENT-RELATED MORTALITY
Authors: M. Pereira, G. Marques, A.-B. Sarmento-Ribeiro
Journal: HemaSphere (2022)

Background: Non-promyelocytic acute myeloblastic leukemia (AML) associates with high mortality rates, with a dismal prognosis; treatment options were unchanged over almost four decades, and recent attempts at improving the outcome of AML patients have included risk-adjusted post-remission consolidation protocols, anthracycline and cytarabine dosing adjustments, the addition of a third active agent to the standard anthracycline-cytarabine doublet protocol and, over the last decade, the addition of targeted agents directed at disease biology. However, even when the addition of a third drug results in improved disease-related outcomes, these improvements may be offset by the increase in treatment-related morbidity and mortality. Aims: To determine whether there is a benefit in terms of early disease control, early toxicity and long-term survival in the addition of a third, non-targeted, drug to anthracycline-cytarabine doublet-based first line induction chemotherapy in adults with AML. Methods: We performed a systematic review and meta-analysis of the published literature; the validity of the analytical method of comparing the addition of any third drug to the same standard treatment has been previously described by the Lung Cancer Group of the Cochrane Collaboration. The methodological quality of each study selected for inclusion was assessed according to the Jadad Scale; publication bias was investigated through Begg’s and Egger’s methods. The pooled risk ratio for the effect size of the triplet protocol compared to the doublet protocol, with a pooled 95% confidence interval, was calculated for each of the outcome variables; both a fixed effects model and a random effects model (for heterogeneous data) were used. Results: Our meta-analysis showed that non-targeted triplet-based regiments induced marginally higher complete remission (CR) rates (RR=1.08, 95% CI: 1.04-1.12), with lower rates of primary refractoriness to treatment (RR=0.78, 95% CI: 0.70-0.87), although inducing higher rates of treatment-related mortality (RR=1.11, 95% CI: 0.95-1.30), with a lack of improvement in overall survival and disease-free survival. Summary/Conclusion: There is a very fragile balance between disease-specific survival and treatment-specific survival with the current doublet protocols, due to their high intrinsic toxicity; decreases in disease-related death through the addition of a third non-targeted drug are often accompanied by increases in treatment-related death secondary to cumulative toxicity. We suggest that the decision to use a non-targeted triplet-based regimen should be patient-adapted, with a preference for doublet protocols in patients at high risk for toxicity and with low risk for refractory disease, and a preference for triplets in patients at low risk for toxicity and high risk for refractory disease.
PB1772: IN-VITRO APOPTOTIC EFFECT OF NATURALLY OCCURRING COMPOUNDS, PIPERINE AND ASCORBIC ACID ON ACUTE MYELOID LEUKAEMAI (AML) CELL LINE.
Authors: R. Aljohani, C. Munialo, S. Bokaee, U. Osadolor, S. Hewamana, T. Lin
Journal: HemaSphere (2022)

Background: AML is a haematological malignancy, which is almost always fatal without treatment with survival ranging from few days to a few weeks. Myeloid cell formation, proliferation and apoptosis are disrupted in AML, caused by a range of genetic and epigenetic abnormalities. Piperine and Ascorbic acid are naturally occurring organic substances with potential anticancer capabilities. In addition various dietary and vitamin supplements are used during anti-cancer treatment. Aims: We evaluated the in-vitro apoptotic effect of naturally occurring organic substances Piperine and Ascorbic acid in comparison to commonly used chemotherapeutic drug Fludarabine on an AML cell line (HL-60 leukaemia cells). Methods: HL-60 cells were cultured in RPMI-1640 media supplemented with 10% (v/v) FBS, 1% (w/v) penicillin/streptomycin at 37°C with 5% CO2. Viability was assessed using trypan blue exclusion. Final concentration of 1 × 106 cells/well achieved using haemocytometer and annexin V-FITC/PI apoptosis was assessed by flow cytometry. Percentage apoptosis calculated at 24h time point using Piperine, Ascorbic acid and Fludarabine alone and in combination. Results: Piperine (50 μM), Ascorbic acid (250 μM) and Fludarabine (50 μM) induced apoptosis in HL-60 cells at 24h time point compared to controls. The combination of Piperine and Ascorbic acid showed higher percentage apoptosis but the percentage apoptosis was significantly lower when Fludarabine was combined with either Piperine (P=0.0003) or Ascorbic acid (P=0.002). Image:Summary/Conclusion: Our data shows interactions of naturally occurring organic compounds and chemotherapeutic agents in inducing in-vitro apoptosis. However, further studies are needed to access the clinical impact of taking naturally occurring organic compounds and chemotherapeutic agents together.
PB1860: CLONALITY RELATEDNESS AND MOLECULAR CHARACTERISTICS OF RICHTER SYNDROME
Authors: Y. Sha, R. Jiang, Y. Miao, T. Qiu, S. Qin, J. Qiu, H. Mi, W. Wu, C. Qiao, Y. Wu, Y. Xia, L. Wang, L. Fan, W. Xu, J. Li, H. Zhu
Journal: HemaSphere (2022)

Background: Richter Syndrome (RS) is defined as the development of an aggressive lymphoma from chronic lymphocytic leukaemia/Small lymphocytic leukemia (CLL/SLL). RS clonally derived from CLL and RS unrelated to the original CLL display distinct pathological and biological entities. Clonally related RS DLBCL patients have extremely pooor prognosis even in the era of novel agents. Therefore, determination of clonality of RS to the underlying CLL is critical for proper management of RS. Aims: To explore the clonality relatedness, clinical and molecular characteristics of patients with RS. Methods: This study retrospectively analyzed 18 RS patients diagnosed in the First Affiliated Hospital of Nanjing Medical University (Pukou CLL center) from January 2019 to December 2021. The immunoglobin heavy variable (IGHV) gene usage and IGHV-D-J rearrangement pattern of diagnosed CLL/SLL and transformed diffuse large B-cell lymphoma (DLBCL) were compared in order to determine the clonality relatedness. Clinical and molecular characteristics of patients when newly diagnosed CLL/SLL and transformed DLBCL were collected to explore the risk factors of RS. Results: The median age of RS was 56.5 (41-75) years old. 17 patients transformed to DLBCL and 1 transformed to Hodgkin lymphoma (HL). Among 17 patients transformed to DLBCL, 15 were clonality related to CLL/SLL while 2 showed clonality unrelated to CLL/SLL. Next-generation sequencing (NGS) analysis of 11 paired initially diagnosed treatment-naïve CLL/SLL and RS DLBCL found that, EGR2、TP53 and NOTCH1 were among the most frequently mutated genes both in treatment-naïve CLL/SLL and in RS DLBCL. The median sample tumor mutational burden (TMB) were 2-hit in treatment-naïve CLL/SLL and 3-hit in RS DLBCL. Certain mutations were acquired or lost during Richter transformation in some patients, indicating clonal evolution. Among 10 patients prior exposure to BTK inhibitors before RS, 4 patients acquired BTK mutation. Above mentioned mutations might be the high risk factors of transformation; Moreover, TP53 and EGR2 mutation in RS DLBCL tissue might be associated with poor prognosis after Richter transformation even in patients treated with the combination of novel drugs. Image:Summary/Conclusion: This study is the first one in China who introduce the methods to analyze the clonality relatedness between RS DLBCL and initial CLL/SLL. Among 17 RS DLBCL patients diagnosed in our center, 15 were clonality relatedness while 2 were clonality unrelatedness. We recommend all qualified centers to evaluated clonality relatedness of RS DLBCL patients. The mutational landscape between initially diagnosed treatment-naïve CLL/SLL and transformed DLBCL showed certain heterogeneity. The molecular mechanism underlying RS remains to be explored further.
PB2206: FULL SPECTRAL FLOW CYTOMETRY ANALYSIS OF THE BONE MARROW IMMUNE MICROENVIRONMENT IN PATIENTS WITH MYELODYSPLASTIC SYNDROME
Authors: M. chen, M. fu, H. Wang
Journal: HemaSphere (2022)

Background: The bone marrow (BM) microenvironment is actively studied in patients with myelodysplastic syndrome (MDS). Full-spectral flow cytometry (FSFCM) is a novel technique that makes it possible to simultaneously study the immune system and malignant cells. Aims: to study the microenvironment and immune checkpoint of MDS by FSFCM. Methods: Retrospective analysis of BM samples from 22 MDS patients and 22 healthy donors who received treatment at the Hebei Yanda Lu Daopei Hospital between January 2020 and September 2020 using 26 parameter FSFCM in a single tube. Multiple immune subsets, myeloblasts and their expression of CD96 and CD200 were also analyzed. Results: The percentage of multiple lymphocytic subsets and number of plasmacytoid dendritic cells (PDCs) were significantly significantly lower in the samples from MDS patients compared to the samples from non-malignant controls.Additionally, expression of the CD96 surface marker were significantly lower on T-cell subsets and CD56bri NK cells,and was significantly higher levels on PDCs in the MDS patient samples compared to the healthy control samples. in the MDS samples CD200 expression on immune cells and myeloblasts were significantly higher in the MDS samples compared to those from healthy controls. The overexpression of CD200 on CD56dim natural killer (NK) cells was an independent risk factor for MDS. Image:Summary/Conclusion: The percentage of immune cells and expression of immune checkpoint proteins on immune cells from BMs of MDS were distinct from that of healthy control samples.
P820: PREDICTING RESPONSE TO RABBIT ATG-BASED INTENSIVE IMMUNOSUPPRESSIVE THERAPY COMBINED WITH ELTROMBOPAG IN CHINESE ADULT PATIENTS WITH SEVERE APLASTIC ANEMIA
Authors: R. Li, Z. Liu, X. Chen, Q. Long, Y. Yang, S. Lin, J. Jia, G. He, J. Li
Journal: HemaSphere (2022)

Background: The intensive immunosuppressive therapy (IST) consisted by antithymocyte immunoglobulin (ATG) and cyclosporin (CsA) combining with eltrombopag (E-PAG) is the initial therapy for adult patients with severe aplastic anemia (SAA). There is rabbit ATG (r-ATG) rather than horse ATG in the mainland of China and E-PAG is recommended with 75mg/d for East Asian population. Aims: To explore factors predicting the efficacy of E-PAG (75mg/d) plus r-ATG based IST for SAA patients in East Asia. Methods: From February 2018 to December 2020, we conducted a retrospective, multicenter study to analyze 58 adult SAA patients with rabbit ATG-based IST and E-PAG in the China Eastern Cooperation Group for Anemia (CECGA). The dosage of r-ATG was 3.5mg·kg-1·d-1 for 5 days with intravenous infusion and CsA was 3-5mg·kg-1·d-1 early in the regimen maintaining concentration at 150-200ng/ml, whose dosage could be modulated on the basis of drug concentration and severe adverse events (SAEs). E-PAG was recommended with 75mg/d at least 6 months. If or SAEs occurred or the count of platelet was higher than 200×109/L, E-PAG would be discontinued. Results: 58 patients with median age of 42.5 years (18 years to 74 years) were treated with r-ATG based IST plus E-PAG. Cohort 1 and cohort 2 included patients with or without a response at 6 months, whist the median age were 50.5 years (24 years to 74 years) and 38 years (18 years to 71 years), separately. The median time between diagnosis and treatment was 3 weeks (1 week to 106 weeks) and 3 weeks (1 week to 166 weeks), respectively. The response rates of E-PAG combining with IST at 3, 6 and 12 months after IST were 64%, 76% and 85% (44 of 52), while the complete response rates at 3, 6 and 12 months were 19%, 21% and 29% (15 of 52), separately. The baseline absolute lymphocyte count (ALC) (area under a curve (AUC)=0.706, 95%CI 0.522-0.890, P=0.057), red cell distribution width – coefficient of variation (RDW-CV) (AUC=0.722, 95%CI 0.494-0.950, P=0.040) and reticulocyte (Ret) percentage (AUC=0.798, 95%CI 0.640-0.956, P=0.006) were highly predictive of response at 6 months (Figure 1). The tipping values of Ret percentage, ALC and RDW-CV were 0.45%, 1.06×109/L and 11.75%, respectively. The sensitivity and specificity of Ret percentage were 81.6% and 66.7%; RDW-CV were 94.7% and 55.6%; ALC were 55.3% and 88.9%. The 2-year overall survival was 93%. Image:Summary/Conclusion: The baseline Ret percentage, RDW-CV and ALC were potential factors to predict a favorable effect in SAA patients of East Aisan.
P796: ENRICHED CD16+ MONOCYTES DRIVE T LYMPHOCYTES CELL RESPONSES IN APLASTIC ANEMIA
Authors: M. Ge, H. Wu, J. Huo, Y. Shao, Y. Zheng
Journal: HemaSphere (2022)

Background: Monocytes, an important component of innate and acquired immunity, encompass three subsets, the classical monocytes (CM, CD14++CD16-), intermediate monocytes (IM, CD14++ CD16+) and nonclassical monocytes (NCM, CD14+CD16++). IM and NCM are collectively referred to CD16+ monocytes, which has been studied in many inflammatory diseases. Whereas, the distribution and function of monocytes in acquired aplastic anemia (AA) remain unclear. Aims: This study aims to determine the distribution of peripheral blood (PB) and bone marrow (B M) monocyte subpopulations in AA and expound the role of CD16+ monocytes on T lymphocytes function. Methods: The proportions of monocyte subsets in the PB and BM of AA patients and healthy donors (HD) were analyzed by flow cytometry. CD16+ monocytes were isolated by magnetic beads and co-cultured with CD3+ T cells, afterwards, the basic biological characteristics of T cells including proliferation, activation and differentiation etc. were evaluated. Results: Results showed that the percentage of CD16+ monocytes in PB and BM was significantly increased in AA patients compared with that in HDs, and the proportion of CM was decreased. However, there was no difference between patients with SAA and NSAA. CD16+ monocytes were further divided into two subgroups, which named IM and NCM. In contrast with HD, the two subgroups were both elevated in AA, mainly the IM. After treatment, NCM and IM were reduced and CM was increased in the patients of complete and partial remission. Then the effect of CD16+ monocytes on T cells function were elaborated. Using a co-culture model, we discovered that CD16+ monocytes in AA patients had stronger ability to promote the proliferation of CD3+ T, CD3+CD4+ T and CD3+CD8+ T cells than that in HDs (Fig 1A, b-d). Furthermore we found that AA-CD16+ monocytes played an important role in the over activation of CD3+CD4+ T and CD3+CD8+ T cells (Fig 1B, b-d). As expected, AA-CD16+ monocytes were extremely potent inducers of Th1、Th17 and cytotoxic T cells (Tc1) differentiation in vitro (Fig 1C, b-d), nevertheless, there was no difference on the effect of monocytes on Treg between AA and HD. Image:Summary/Conclusion: This study provided that the expanded CD16+ monocytes, including NCM and IM，had a major role in driving T cell responses in AA patients.
P1016: POLYCYTHEMIA VERA AND IMMUNE THROMBOGENESIS
Authors: R. Cacciola, V. Vecchio, E. Gentilini Cacciola, E. CACCIOLA
Journal: HemaSphere (2022)

Background: Polycythemia Vera (PV) is a Ph1-negative myeloproliferative neoplasm characterized by vascular thrombosis and poor survival. The polycythemic thrombogenesis is associated with erythrocytosis and red cell adhesiveness angiopathy. Recent studies reported a JAK/STAT-mediated reduction of the regulatory T cells (Tregs) (CD4+, CD25high, CD127low, FoxP3+) and loss of self-tolerance. Aims: We investigated Tregs, anti-endothelial cell antibodies (AECA), and endothelial, platelet and coagulation activation, in Polycythemia Vera (PV) and thrombosis. Methods: We enrolled 60WHO-defined PV patients (30 men, 30 women; mean age 45±10 years) without cardiovascular risk factors, autoimmune disease or thrombotic history. Of PV patients, 40/60 had thromosis includingmyocardial infarction (MI) (10/60) according to the WHO critera, deep vein thrombosis (20/60) and pulmonary embolism (10/60) on lower-limb ultrasonography and computed tomography angiography, respectively. All patients were evaluated for JAK2V617F allele burden, Tregs, AECA,Endothelial Leukocyte Adhesion Molecule-1 (ELAM-1), Intercellular Adhesion Molecule-1 (ICAM-1),prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (Fib) and D-dimer (DD). JAK2V617F allele burden were analyzed by Polymerase chain reaction, Tregs were measured by flow cytometry,AECA, ELAM-1 and ICAM-1 by ELISA, PT and APTT by coagulometric test, Fib using Clauss method, and DD using ELISA.Complete blood hemostasis was studied by PFA-100 on Collagen/ADP (CT-ADP) and Collagen/Epinephrine (CT-EPI) cartridges and Thromboelastometry method on Clotting Time (CT), Clotting Formation Time (CFT), Maximum Clot Firmness (MCF), and clot lysis at 30 minutes (LY-30). Results: The patients with thrombosis had JAK2V616F allele burden higher (> 50%) compared to patients without thrombosis (< 50Kroll%), lower Tregs (1,5±0,5% vs 3.5±1%),higher AECA (200±20% vs 110±10%), ELAM-1 (80±10 ng/ml vs 45±5 ng/ml), and ICAM (170 ng/mL±10 vs 110±10 ng/mL), longer PT (30±10 s vs 20±2 s) and PTT (60±10 s vs 38±5 s), lower Fib (90±20 mg/dl vs 120±20 mg/dl), higher DD (650±100 mg/l vs 300±50 mg/l) and shorter C/ADP and C/EPI (C/ADP, n.v. 68-121 s (40±10 s vs 55±20 s) and C/EPI n.v. 84-160 s (35±5 s vs 60±10 s). The patients with thrombosis had shorter CT (INTEM 35±20 s vs 70±20 s, EXTEM 20±10 s vs 30±5 s), shorter CFT (INTEM 15±10 s vs 25±5 s EXTEM 18±10 s vs 28±5 s), longer MCF (INTEM 130±10 mm vs 90±10 mm, EXTEM 120±10 mm vs 82±10 mm), and lower LY-30 (INTEM 0.9% vs 15%, EXTEM 0.8% vs 15%). A positive correlation there was between Tregs and AECA, ELAM-1 and ICAM-1 and thrombosis. Summary/Conclusion: These findings shed new light on thrombotic pathogenesis in patients with PV.
PB1928: ALLOGENEIC STEM CELL TRANSPLANTATION FOR ADULT CHRONIC MYELOMONOCYTIC LEUKEMIA IN THE MOLECULAR ERA
Authors: T. Zhang
Journal: HemaSphere (2022)

Background: Allogeneic hematopoietic cell transplantation (allo-HSCT) is potentially curative for patients with chronic myelomonocytic leukemia (CMML), however, few data exist regarding prognostic factors and transplant outcomes regarding Chinese. Aims: To review the updated trends of myeloablative conditioning practice and outcomes in allo-HSCT to treat CMML, we retrospectively evaluated 40 patients who underwent myeloablative conditioning regimen followed by allo-HSCT between January 2009 to December 2021. Methods: The CMML-specific prognostic scoring system (CPSS) has been validated in subjects receiving non-transplant therapy and was included in our study. From 2009–2021, there were 40 adult subjects who received allo-HSCT for CMML. Results: After the median duration of follow-up was 36.9 months (range, 3 to 156 months), the overall survival (OS) and disease-free survival (DFS) were 65.0% and 47.5% respectively. The median age at allo-HSCT was 47 years (range, 20 to 59 years). Thirty-five percent of the patients had HLA-haploidentical donors, 62.5% had HLA-identical sibling donors, and 2.5% had matched unrelated donors. The cumulative incidence of grade II-IV acute graft-versus-host disease (aGVHD) was 30.0%, and that of extensive chronic GVHD (cGVHD) was 25.0%. The cumulative incidence of relapse was 32.5%, the non-relapse mortality (NRM) was 20.0%. Eighteen patients harbored at least one gene mutation detected by Next-generation sequencing (NGS) mutation analysis. In addition, according to the number of gene mutations, the patients could be divided into groups with 0, 1-2 and ≥3 gene mutations, and the 3-year DFS of the three groups were 68.2%, 27.3%, and 14.3% respectively (P=0.010). Furthermore, the achievement of a complete remission (CR) before allo-HSCT was associated with longer OS and DFS (3-year OS: 74.2% vs 33.3%, P=0.016; 3-year DFS: 58.1% vs 11.1%, P=0.017). Those with minimal residual disease (MRD+) by FACS or PCR have a significantly worse prognosis compared to patients with no evidence of MRD (MRD−) at the time of allo-HSCT (3-year OS: 52.4% vs 78.9%, P=0.026; 3-year DFS: 28.6% vs 68.4%, P=0.009). In multivariate analysis, the depth of remission before allo-HSCT was identified as significant risk factors for OS; Meanwhile, MRD and gene mutation were independent predictors of DFS. Image:Summary/Conclusion: Taken together, this retrospective analysis reports updated trends in allo-HSCT for CMML in China and identifies pre-transplantation factors influencing post-transplantation outcomes. Whether prophylactic use of emerging agents, such as azacitidine, can reduce post-transplant relapse rates remains to be further explored in prospective studies.